The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient. This invention also relates to pharmaceutical compositions comprising these prodrugs. The prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.
Aspartyl protease inhibitors are considered the most effective current drug in the fight against HIV infection. These inhibitors, however, require certain physicochemical properties in order to achieve good potency against the enzyme. One of these properties is high hydrophobicity. Unfortunately, this property results in poor aqueous solubility and low oral bioavailability.
U.S. Pat. No. 5,585,397 describes a class of sulfonamide compounds that are inhibitors of the aspartyl protease enzyme. These compounds illustrate the drawbacks concomitant to pharmaceutical compositions comprising hydrophobic aspartyl protease inhibitors. For example, VX-478 (4-amino-N-((2-syn,3S)-2-hydroxy-4-phenyl-3((S)-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl-N-isobutyl-benzenesulfonamide) is an aspartyl protease inhibitor disclosed in the ""397 patent. It has a relatively low aqueous solubility. While the oral bioavailability of this inhibitor in a xe2x80x9csolutionxe2x80x9d formulation is excellent, the dosage of VX-478 in this form is severely limited by the amount of liquid present in the particular liquid dosage from, e.g., encapsulated into a soft gelatin capsule. A higher aqueous solubility would increase drug load per unit dosage of VX-478.
Currently, the solution formulation of VX-478 produces an upper limit of 150 mg of VX-478 in each capsule. Given a therapeutic dose of 2400 mg/day of VX-478, this formulation would require a patient to consume 16 capsules per day. Such a high pill burden would likely result in poor patient compliance, thus producing sub-optimal therapeutic benefit of the drug. The high pill burden is also a deterrent to increasing the amount of the drug administered per day to a patient. Another drawback of the pill burden and the concomitant patient compliance problem is in the treatment of children infected with HIV.
Furthermore, these xe2x80x9csolutionxe2x80x9d formulations, such as the mesylate formulation, are at a saturation solubility of VX-478. This creates the real potential of having the drug crystallize out of solution under various storage and/or shipping conditions. This, in turn, would likely result in a loss of some of the oral bioavailability achieved with VX-478.
One way of overcoming these problems is to develop a standard solid dosage form, such as a tablet or a capsule or a suspension form. Unfortunately, such solid dosage forms have much lower oral bioavailability of the drug.
Thus, there is a need to improve the drug load per unit dosage form for aspartyl protease inhibitors. Such an improved dosage form would reduce the pill burden and increase patient compliance. It would also provide for the possibility of increasing the amounts of the drug administered per day to a patient.
The present invention provides novel prodrugs of a class of sulfonamide compounds that are inhibitors of aspartyl protease, in particular, HIV aspartyl protease. These prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. The present invention also provides pharmaceutical compositions comprising these prodrugs and methods of treating HIV infection in mammals using these prodrugs and the pharmaceutical compositions thereof.
These prodrugs can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
It is a principal object of this invention to provide a novel class of prodrugs of sulfonamide compounds that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This novel class of sulfonamides is represented by formula I: 
wherein:
A is selected from H; Ht; xe2x80x94R1xe2x80x94Ht; xe2x80x94R1xe2x80x94C1-C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2)2; xe2x80x94R1xe2x80x94C2-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2)2; or R7;
each R1 is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94S(O)2, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94 or xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(O)xe2x80x94;
each Ht is independently selected from C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, xe2x80x94OR2, SR2, xe2x80x94R2, xe2x80x94N(R2)(R2), xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Q, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2(R2) , halo, xe2x80x94CF3, xe2x80x94NO2, Q, xe2x80x94OQ, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94R7, xe2x80x94N(R2)(R7) or xe2x80x94N(R7)2;
each R2 is independently selected from H, or C1-C4 alkyl optionally substituted with Q;
B, when present, is xe2x80x94N(R2)xe2x80x94C(R3)2xe2x80x94C(O)xe2x80x94;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C5-C6 cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)nxe2x80x94N(R2)(R2), Ht, xe2x80x94CN, xe2x80x94SR2, xe2x80x94CO2R2, NR2xe2x80x94C(O)xe2x80x94R2;
each n is independently 1 or 2;
G, when present, is selected from H, R7 or C1-C4 alkyl, or, when G is C1-C4 alkyl, G and R7 are bound to one another either directly or through a C1-C3 linker to form a heterocyclic ring; or
when G is not present (i.e., when x in (G)x is 0), then the nitrogen to which G is attached is bound directly to the R7 group on xe2x80x94OR7;
D and Dxe2x80x2 are independently selected from Q; C1-C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C2-C4 alkenyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C3-C6 cycloalkyl, which is optionally substituted with or fused to Q; or C5-C6 cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n or N(R2); wherein Q is optionally substituted with one or more groups selected from oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, halo or xe2x80x94CF3;
E is selected from Ht; Oxe2x80x94Ht; Htxe2x80x94Ht; xe2x80x94Oxe2x80x94R3; xe2x80x94N(R2)(R3); C1-C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht; C2-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3-C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or C5-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from xe2x80x94OR2, xe2x80x94SR2, xe2x80x94C(O)xe2x80x94NHR2, xe2x80x94S(O)2xe2x80x94NHR2, halo, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R2, xe2x80x94N(R2)2 or xe2x80x94CN;
each R7 is independently selected from 
wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, xe2x80x94N(R2)4, C1-C12-alkyl, C2-C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group, other than the xe2x80x94CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, xe2x80x94R2, N(R2)2, N(R2)3, R2OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, S(O)2xe2x80x94N(R2)2, N(R2)xe2x80x94C(O)xe2x80x94R2, C(O)R2, xe2x80x94S(O)nxe2x80x94R2, OCF3, xe2x80x94S(O)nxe2x80x94R6, N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Mxe2x80x2 is H, C1-C12-alkyl, C2-C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)2, N(R2)3, xe2x80x94R2OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94R6, xe2x80x94N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Z is CH2, O, S, N(R2)2, or, when M is absent, H;
Y is P or S;
X is O or S; and
R9 is C(R2)2, O or N(R2); and wherein when Y is S, Z is not S; and
R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, Oxe2x80x94C1-C4 alkyl or OC(O)C1-C4 alkyl.
It is a also an object of this invention to provide pharmaceutical compositions comprising the sulfonamide prodrugs of formula I and methods for their use as prodrugs of HIV aspartyl protease inhibitors.
In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:
The following terms are employed herein:
Unless expressly stated to the contrary, the terms xe2x80x9cxe2x80x94SO2xe2x80x94xe2x80x9d and xe2x80x9cxe2x80x94S(O)2xe2x80x94xe2x80x9d as used herein refer to a sulfone or sulfone derivative (i.e., both appended groups linked to the S), and not a sulfinate ester.
For the compounds of formula I, and intermediates thereof, the stereochemistry of OR7 is defined relative to D on the adjacent carbon atom, when the molecule is drawn in an extended zig-zag representation (such as that drawn for compounds of formula XI, XV, XXII, XXIII and XXXI). If both OR7 and D reside on the same side of the plane defined by the extended backbone of the compound, the stereochemistry of OR7 will be referred to as xe2x80x9csynxe2x80x9d. If OR7 and D reside on opposite sides of that plane, the stereochemistry of OR7 will be referred to as xe2x80x9cantixe2x80x9d.
The term xe2x80x9carylxe2x80x9d, alone or in combination with any other term, refers to a carbocyclic aromatic radical containing the specified number of carbon atoms.
The term xe2x80x9cheterocyclicxe2x80x9d refers to a stable 5-7 membered monocycle or 8-11 membered bicyclic heterocycle which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms xe2x80x9cnitrogen and sulfur heteroatomsxe2x80x9d include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. The heterocyclic ring may be attached by any heteroatom of the cycle which results in the creation of a stable structure. Preferred heterocycles defined above include, for example, benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, xcex2-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrroldinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazoyl, benzodioxolyl, thiophenyl, tetrahydrothiophenyl and sulfolanyl.
The terms xe2x80x9cHIV proteasexe2x80x9d and xe2x80x9cHIV aspartyl proteasexe2x80x9d are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d refers to an amount effective in treating HIV infection in a patient. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to an amount effective in preventing HIV infection in a patient. As used herein, the term xe2x80x9cpatientxe2x80x9d refers to a mammal, including a human.
The term xe2x80x9cpharmaceutically acceptable carrier or adjuvantxe2x80x9d refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94(C1-4 alkyl)4+ salts.
The term xe2x80x9cthiocarbamatesxe2x80x9d refers to compounds containing the functional group Nxe2x80x94SO2xe2x80x94O.
The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. The explicitly shown hydroxyl is also preferred to be syn to D, in the extended zigzag conformation between the nitrogens shown in compounds of formula I.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term xe2x80x9cstablexe2x80x9d, as used herein, refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrox-yethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The novel sulfonamides of this invention are those of formula I: 
wherein:
A is selected from H; Ht; xe2x80x94R1xe2x80x94Ht; xe2x80x94R1xe2x80x94C1-C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2)2; xe2x80x94R1xe2x80x94C2-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2)2; or R7;
each R1 is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94S(O)2, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94 or xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(O)xe2x80x94;
each Ht is independently selected from C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, xe2x80x94OR2, SR2, xe2x80x94R2, xe2x80x94N(R2)(R2), xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Q, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, xe2x80x94NO2, Q, xe2x80x94OQ, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94R7, xe2x80x94N(R2)(R7) or xe2x80x94N(R7)2;
each R2 is independently selected from H, or C1-C4 alkyl optionally substituted with Q;
B, when present, is xe2x80x94N(R2)xe2x80x94C(R3)2xe2x80x94C(O)xe2x80x94;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C5-C6 cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)nxe2x80x94N(R2)(R2) Ht, xe2x80x94CN, xe2x80x94SR2, xe2x80x94CO2R2, NR2xe2x80x94C(O)xe2x80x94R2;
each n is independently 1 or 2;
G, when present, is selected from H, R7 or C1-C4 alkyl, or, when G is C1-C4 alkyl, G and R7 are bound to one another either directly or through a C1-C3 linker to form a heterocyclic ring; or
when G is not present (i.e., when x in (G)x is 0), then the nitrogen to which G is attached is bound directly to the R7 group in xe2x80x94OR7 with the concomitant displacement of one xe2x80x94ZM group from R7;
D and Dxe2x80x2 are independently selected from Q; C1-C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C2-C4 alkenyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C3-C6 cycloalkyl, which is optionally substituted with or fused to Q; or C5-C6 cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n or N(R2); wherein Q is optionally substituted with one or more groups selected from oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, halo or xe2x80x94CF3;
E is selected from Ht; Oxe2x80x94Ht; Htxe2x80x94Ht; xe2x80x94Oxe2x80x94R3; xe2x80x94N(R2)(R3); C1-C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht; C2-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3-C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or C5-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from xe2x80x94OR2, xe2x80x94SR2, xe2x80x94C(O)xe2x80x94NHR2, xe2x80x94S(O)2xe2x80x94NHR2, halo, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R2, xe2x80x94N(R2)2 or xe2x80x94CN;
each R7 is independently selected from 
wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, xe2x80x94N(R2)4, C1-C12-alkyl, C2-C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group, other than the xe2x80x94CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, xe2x80x94R2, N(R2)2, N(R2)3, R2OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, S(O)2xe2x80x94N(R2)2, N(R2)xe2x80x94C(O)xe2x80x94R2, C(O)R2, xe2x80x94S(O)nxe2x80x94R2, OCF3, xe2x80x94S(O)nxe2x80x94R6, N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Mxe2x80x2 is H, C1-C12-alkyl, C2-C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)2, N(R2)3, xe2x80x94R2OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94R6, xe2x80x94N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Z is CH2, O, S, N(R2)2, or, when M is not present, H.
Y is P or S;
X is O or S; and
R9 is C(R2)2, O or N(R2); and wherein when Y is S, Z is not S; and
R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, Oxe2x80x94C1-C4 alkyl or Oxe2x80x94C(O)xe2x80x94C1-C4 alkyl.
Preferably, at least one R7 is selected from: 
-(L)-lysine, xe2x80x94PO3Na2, 
-(L)-tyrosine, 
xe2x80x94PO3Mg, xe2x80x94PO3(NH4)2, xe2x80x94CH2xe2x80x94OPO3Na2, 
-(L)-serine, xe2x80x94SO3Na2, 
xe2x80x94SO3Mg, xe2x80x94SO3(NH4)2, xe2x80x94CH2OSO3Na2, xe2x80x94CH2xe2x80x94OSO3(NH4)2, 
acetyl, 
-(L)-valine, -(L)-glutamic acid, -(L)-aspartic acid, -(L)-xcex3-t-butyl-aspartic acid, 
-(L)-(L)-3-pyridylalanine, -(L)-histidine, xe2x80x94CHO, 
PO3K2, PO3Ca, PO3-spermine, PO3-(spermidine)2 or PO3-(meglamine)2.
It will be understood by those of skill in the art that component M or Mxe2x80x2 in the formulae set forth herein will have either a covalent, a covalent/zwitterionic, or an ionic association with either Z or R9 depending upon the actual choice for M or Mxe2x80x2. When M or Mxe2x80x2 is hydrogen, alkyl, alkenyl, or R6, M or Mxe2x80x2 is covalently bound to R9 or Z. If M is a mono- or bivalent metal or other charged species (i.e., NH4+), there is an ionic interaction between M and Z and the resulting compound is a salt.
When x is 0 in (M)x, Z may be a charged species. When that occurs, the other M may be oppositely charged to produce a 0 net charge on the molecule. Alternatively, the counter ion may located elsewhere in the molecule.
Except where expressly provided to the contrary, as used herein, the definitions of variables A, R1-R4, R6-R9, Ht, B, x, n, D, Dxe2x80x2, M, Q, X, Y, Z and E are to be taken as they are defined above for the compounds of formula I.
According to a preferred embodiment, the compounds of this invention are those represented by formulas XXII, XXIII or XXXI: 
wherein A, R3, R7, Ht, D, Dxe2x80x2, x, E are as defined above for compounds of formula I. For ease of reference, the two R3 moieties present in formula XXXI have been labeled R3 and R3xe2x80x2.
For compounds of formula XXII, more preferred compounds are those wherein:
A is selected from 3-tetrahydrofuryl-Oxe2x80x94C(O)xe2x80x94, 3-(1,5-dioxane)-Oxe2x80x94C(O)xe2x80x94, or 3-hydroxy-hexahydrofura[2,3-b]-furanyl-Oxe2x80x94C(O)xe2x80x94;
Dxe2x80x2 is C1-C4 alkyl which is optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Q and Q;
E is C6-C10 aryl optionally substituted with one or more substituents selected from oxo, xe2x80x94OR2, SR2, xe2x80x94R2, xe2x80x94N(R2)2, xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Q, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, xe2x80x94NO2, Q, xe2x80x94OQ, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94R7, xe2x80x94N(R2)(R7) or xe2x80x94N(R7)2; or a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from xe2x80x94CH3, R4, or Ht.
Ht, insofar as it is defined as part of R3, is defined as above except for the exclusion of heterocycles; and
all other variables are as defined for formula I.
Even more preferred are compounds of formula XXII, wherein A is 3-tetrahydrofuryl-Oxe2x80x94C(O)xe2x80x94; G is hydrogen; Dxe2x80x2 is isobutyl; E is phenyl substituted with N(R7)2; each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, C1-C4 alkyl or xe2x80x94N(R2)4; and each Mxe2x80x2 is H or C1-C4 alkyl.
Another preferred embodiment for the formula XXII compounds are those wherein:
E is a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from xe2x80x94CH3, R4, or Ht; and
all other variables are as defined for formula I.
Even more preferred are any of the formula XXII compounds set forth above, wherein R7 in xe2x80x94OR7 is xe2x80x94PO(OM)2 or C(O)CH2OCH2CH2OCH2CH2OCH3 and both R7 in xe2x80x94N(R7)2 are H, wherein M is H, Li, Na, K or C1-C4 alkyl; or wherein R7 in xe2x80x94OR7 is C(O)CH2OCH2CH2OCH3, one R7 in xe2x80x94N(R7)2 is C(O)CH2OCH2CH2OCH3 and the other is H.
The most preferred compound of formula XXII has the structure: 
For compounds of formula XXIII, most preferred compounds are those wherein:
R3 is C1-C6 alkyl, C2-C6 alkenyl, C5-C6 cycloalkyl, C5-C6 cycloalkenyl or a 5-6 membered saturated or unsaturated heterocycle, wherein any member of said R3 may be optionally substituted with one or more substituents selected from the group consisting of xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)nN(R2)(R2), Ht, xe2x80x94CN, xe2x80x94SR2, xe2x80x94C(O)2R2 and NR2xe2x80x94C(O)xe2x80x94R2; and
Dxe2x80x2 is C1-C3 alkyl or C3 alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94Oxe2x80x94Q and Q (with all other variables being defined as above for compounds of formula I).
Even more preferred are compounds of formula XXIII described above, wherein R7 is xe2x80x94PO(OM)2 or xe2x80x94C(O)xe2x80x94Mxe2x80x2.
For compounds of formula XXXI, most preferred compounds are those wherein A is R1xe2x80x94Ht, each R3 is independently C1-C6 alkyl which may be optionally substituted with a substituent selected from the group consisting of xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)nN(R2)(R2), Ht, xe2x80x94CN, xe2x80x94SR2, xe2x80x94CO2R2 or xe2x80x94NR2xe2x80x94C(O)xe2x80x94R2; and Dxe2x80x2 is C1-C4 alkyl, which may be optionally substituted with a group selected from the group consisting of C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94Oxe2x80x94Q; and E is Ht, Htxe2x80x94Ht and xe2x80x94NR2R3.
Even more preferred are those compounds of formula XXXI described above wherein R7 is xe2x80x94PO(OM)2 or xe2x80x94C(O)xe2x80x94Mxe2x80x2.
According to another embodiment, the invention provides compounds of the following formulae: 
wherein, in compound 1005, when R7 is PO3M, (G)x is not H; and wherein R10 is selected from isopropoyl or cyclopentyl; R11 is selected from NHR7 or OR7; and x, R7 and G are as defined above.
The prodrugs of the present invention may be synthesized using conventional synthetic techniques. U.S. Pat. No. 5,585,397 discloses the synthesis of compounds of formula: 
wherein A, B, n, D, Dxe2x80x2, and E are as defined above. Prodrugs of formula (I) of the present invention can be readily synthesized from the ""397 compounds using conventional techniques. One of skill in the art would be well aware of conventional synthetic reagents to convert the xe2x80x94OH group of the ""397 compounds to a desired xe2x80x94OR7 functionality of the present invention, wherein R7 is as defined above. The relative ease with which the compounds of this invention can be synthesized represents an enormous advantage in the large scale production of these compounds.
For example, VX-478, a compound disclosed in the ""397 patent, can be readily converted to the corresponding bis-phosphate ester derivative, as shown below: 
Alternatively, if the monophosphate ester of VX-478 is desired, then the synthetic scheme can be readily adapted by beginning with the 4-nitrophenyl derivative of VX-478, as shown below: 
Examples of specific compounds in addition to VX-478 which may be converted to the prodrugs of this invention by similar techniques (and the syntheses of those intermediates to the compounds of the present invention) are disclosed in WO 94/05639 and WO 96/33184, the disclosures of which are herein incorporated by reference.
Pharmaceutically acceptable salts of the compounds of the present invention may be readily prepared using known techniques. For example, the disodium salt of the mono-phosphate ester shown above can be prepared as shown below: 
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
Without being bound by theory, we believe that two different mechanisms are involved in converting the prodrugs of this invention into the active drug, depending upon the structure of the prodrug. The first mechanism involves the enzymatic or chemical transformation of the prodrug species into the active form. The second mechanism involves the enzymatic or chemical cleavage of a functionality on the prodrug to produce the active compound.
The chemical or enzymatic transformation can involve to transfer of a functional group (i.e., R7) from one heteroatom within the molecule to another heteroatom. This transfer is demonstrated in the chemical reactions shown below: 
The cleavage mechanism is demonstrated by the reaction below where a phosphate ester-containing prodrug is converted into the active form of the drug by removal of the phosphate group. 
These protease inhibitors and their utility as inhibitors of aspartyl proteases are described in U.S. Pat. No. 5,585,397, the disclosure of which is incorporated herein by reference.
The prodrugs of the present invention are characterized by unexpectedly high aqueous solubility. This solubility facilitates administration of higher doses of the prodrug, resulting in a greater drug load per unit dosage. The prodrugs of the present invention are also characterized by facile hydrolytic cleavage to release the active aspartyl protease inhibitor in vivo. The high aqueous solubility and the facile in vivo metabolism result in a greater bioavailability of the drug. As a result, the pill burden on a patient is significantly reduced.
The prodrugs of this invention may be employed in a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example, a prodrug of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally-infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
Alternatively, the prodrugs of this invention may be used in vaccines and methods for protecting individuals against viral infection over an extended period of time. The prodrugs may be employed in such vaccines either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of protease inhibitors in vaccines. For example, a prodrug of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period time against HIV infection. As such, the novel protease inhibitors of this invention can be administered as agents for treating or preventing HIV infection in a mammal.
The prodrugs of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other anti-viral agents which interfere with the replication cycle of HIV. By administering the compounds of this invention with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds is potentiated. For instance, the co-administered anti-viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA. Anti-HIV agents targeting such early life cycle events include, didanosine (ddI), alcitabine (ddC), d4T, zidovudine (AZT), polysulfated polysaccharides, sT4 (soluble CD4), ganiclovir, dideoxycytidine, trisodium phosphonoformate, eflor-nithine, ribavirin, acyclovir, alpha interferon and tri-menotrexate. Additionally, non-nucleoside inhibitors of reverse transcriptase, such as TIBO or nevirapine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase.
Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication. The use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy. These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity. In particular, we have discovered that these prodrugs act synergistically in preventing the replication of HIV in human T cells. Preferred combination therapies include the administration of a prodrug of this invention with AZT, ddI, ddC or d4T.
Alternatively, the prodrugs of this invention may also be co-administered with other HIV protease inhibitors such as Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) and A-80,987 (Abbott) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
We prefer administering the prodrugs of this invention as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT, or other HIV aspartyl protease inhibitors. We believe that the co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely eliminating viral infectivity and its associated symptoms.
The prodrugs of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO); and antibiotics (e.g., pentamidine isethiorate) to prevent or combat infection and disease associated with HIV infections, such as AIDS and ARC.
When the prodrugs of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of a prodrug of this invention and another therapeutic or prophylactic agent.
Although this invention focuses on the use of the prodrugs disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events in their life cycle. These viruses include, as well as other AIDS-like diseases caused by retroviruses, such as simian immunodeficiency viruses, but are not limited to, HTLV-I and HTLV-II. In addition, the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelin precursors.
Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 50 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
Upon improvement of a patient""s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient""s disposition to the infection and the judgment of the treating physician.